Gut dysbiosis contributes to the development of depression-like behaviors through abnormal microglia-mediated synaptic pruning driven by complement C3. The study found that chronic unpredictable mild stress (CUMS) in mice led to depression-like behavior, cognitive impairment, and gut dysbiosis, characterized by increased Proteobacteria and elevated microbiota-derived lipopolysaccharides (LPS). Complement C3 activation and aberrant synaptic pruning in microglia were observed, with CUMS-induced gut microbiota transplantation into specific pathogen-free and germ-free mice inducing similar depression-like behaviors. Antidepressants and fecal microbiota transplantation from treated donors improved depression-like behaviors and restored gut microbiome disturbances, along with reduced complement C3/CR3 pathway activation and corrected synaptic pruning. These findings suggest that gut dysbiosis drives depression-like behaviors via complement C3-mediated microglia synaptic pruning, and targeting this pathway could be a key strategy for treating depression. The study also highlights the role of gut microbiota in modulating the complement system and synaptic pruning, with antidepressants like XYS restoring gut microbiota balance and reducing inflammation. Fecal microbiota transplantation from CUMS-induced mice caused depression-like behaviors, while XYS-FMT alleviated depression but not anxiety-like behaviors, indicating that gut dysbiosis is a critical factor in depression pathogenesis. The study further demonstrates that dysregulated gut microbiota contributes to colonic inflammation and barrier disruption, which can be mitigated by antidepressants through restoration of gut microbiota balance. Overall, the research underscores the complex interplay between gut microbiota, the complement system, and microglial synaptic pruning in the pathogenesis of depression.Gut dysbiosis contributes to the development of depression-like behaviors through abnormal microglia-mediated synaptic pruning driven by complement C3. The study found that chronic unpredictable mild stress (CUMS) in mice led to depression-like behavior, cognitive impairment, and gut dysbiosis, characterized by increased Proteobacteria and elevated microbiota-derived lipopolysaccharides (LPS). Complement C3 activation and aberrant synaptic pruning in microglia were observed, with CUMS-induced gut microbiota transplantation into specific pathogen-free and germ-free mice inducing similar depression-like behaviors. Antidepressants and fecal microbiota transplantation from treated donors improved depression-like behaviors and restored gut microbiome disturbances, along with reduced complement C3/CR3 pathway activation and corrected synaptic pruning. These findings suggest that gut dysbiosis drives depression-like behaviors via complement C3-mediated microglia synaptic pruning, and targeting this pathway could be a key strategy for treating depression. The study also highlights the role of gut microbiota in modulating the complement system and synaptic pruning, with antidepressants like XYS restoring gut microbiota balance and reducing inflammation. Fecal microbiota transplantation from CUMS-induced mice caused depression-like behaviors, while XYS-FMT alleviated depression but not anxiety-like behaviors, indicating that gut dysbiosis is a critical factor in depression pathogenesis. The study further demonstrates that dysregulated gut microbiota contributes to colonic inflammation and barrier disruption, which can be mitigated by antidepressants through restoration of gut microbiota balance. Overall, the research underscores the complex interplay between gut microbiota, the complement system, and microglial synaptic pruning in the pathogenesis of depression.